One of many known methods of achieving sustained delivery of a drug is by incorporating the drug in a solid polymeric matrix formed from a bioerodible polymer. Formulations of this type are primarily used for parenteral administration. The matrix may assume a variety of forms, but most often is either in the shape of thin rods suitable for injection, or microscopic particles suitable for application as a dry sprinkle or in a suitable liquid vehicle for injection.
The term "bioerodible" refers to the quality of the polymer that causes it to be degraded or eroded in vivo. This occurs either through enzymatic action or other types of action, and decomposes the polymer into biocompatible, non-toxic by-products which are further metabolized or excreted from the body through the normal physiological pathways, without raising an immunological reaction.
Among the wide variety of polymers having this quality, some which are of particular interest in this invention are poly(orthoester)s and poly(orthocarbonate)s. Such bioerodible polymers are disclosed in Schmitt, U.S. Pat. No. 4,070,347, Jan. 24, 1978; Choi, et al., U.S. Pat. No. 4,093,709, Jun. 6, 1978; Schmitt, U.S. Pat. No. 4,122,158, Oct. 24, 1978; Choi, et el., U.S. Pat. No. 4,131,648, Dec. 26, 1978; Choi, et al., U.S. Pat. No. 4,138,344, Feb. 6, 1979; Schmitt, U.S. Pat. No. 4,155,992, May 22, 1979; Choi, et al., U.S. Pat. No. 4,180,646, Dec. 25, 1979; Capozza, U.S. Pat. No. 4,322,323, Mar. 30, 1982; and Schmitt, U.S. Pat. No. 4,346,709, Aug. 31, 1982. The disclosures in these patents are incorporated herein by reference.
Other bioerodible polymers which are of interest in this invention are poly(lacticacid), poly(glycolic acid) and copolymers of lactic acid and glycolic acid. Published literature relevant to these polymers are Schmitt, et al., U.S. Pat. No. 3,991,766, issued Nov. 16, 1976; Yoles, S., et al., Polymer News 1(4/5):9-15 (1971); Kulkarni, R. K., et al., J. Biomed. Mater. Res. 5:169-181 (1971); and Wise, D. L., Acta Pharm. Suecica 13 (suppl.):34 (1976).
In Shih et al., Journal of Controlled Release 15:55-63 (Feb. 1990), "Acid Catalyzed poly(orthoester) Matrices for Intermediate Term Drug Delivery," the in vitro release of timolol maleate from poly(orthoester) matrices with lipophilic acid catalysts was studied.
In U.S. Pat. No 4,780,319 carboxylic acids are incorporated into polymers to catalyze the erosion of the polymer matrix. Poly(orthoesters), poly(orthocarbonates), polymers of ketenacetal and polyols, polyacetals, polyketals, polyacetates, polyglycolates and polycaprolactones are listed as the possible polymers.
In U.S. Pat. No. 4,346,709 erodible devices comprising a poly(orthoester) or poly(orthocarbonate), a drug and an erosion rate modifier are disclosed. The erosion rate modifiers can either increase or decrease the rate of erosion.
In these formulations in general, the drug is originally dispersed in and held immobile by the polymeric matrix, and the release of the drug from the matrix occurs gradually over a period of time. This sustained release is achieved by one or a combination of mechanisms, including diffusion of the drug through molecular interstices in the polymer, diffusion of the drug through pores in the polymer (if a pore-forming ingredient has been used in the formation of the polymer), and degradation of the polymer itself. The release rate may be controlled to a certain-degree by varying certain system parameters, such as the size and shape of the polymer systems, the choice of polymer used to form the matrix, the molecular weight and density of the polymer, the ratio of drug to polymer, the pore structure of the matrix, the inclusion of additional components such as erosion rate modifiers in the matrix, and the choice of carrier vehicle where one is used.
Degradation of the polymer is potentially the greatest contributing factor to the release of the drug, since degradation reduces and ultimately removes the diffusion barriers which retard the passage of the drug through the matrix. Also, there are certain drugs which are released from the matrix primarily by erosion or degradation of the polymer and not by diffusion. Theoretically, therefore, the release rate may be regulated either up or down by increasing or decreasing the polymer degradation rate. Attempts to do this in the prior art have involved the inclusion of erosion rate modifiers as additives mixed in with the polymers, the modifiers selected either to promote or to inhibit the degradation reaction. Disclosures of erosion rate modifiers and their use appear in Schmitt, U.S. Pat. No. 4,346,709, Aug. 31, 1982, which discloses metals, metal oxides, metal oxide salts, metal hydroxides, amines, organic and inorganic acids, and monobasic and polybasic acids, and Capozza, U.S. Pat. No. 4,322,323, Mar. 30, 1982, which discloses anionic, cationic and nonionic surfactants.
Modifiers known to the prior art are not always a satisfactory solution, however, since under certain circumstances the modifiers tend to diffuse out of the polymer into the surrounding medium. This causes a sharp drop in the effectiveness of the modifier, and the resulting curve of the release rate of the drug vs. time changes in slope. This is particularly the case with highly water-soluble modifiers. When such a water-soluble modifier is a degradation inhibitor, for example, the desired slow release rate lasts only through the initial stages of the release period and is followed by release at a rate which is faster than desired. Conversely, when such a modifier is a degradation promoter, the desired fast release lasts only initially, leaving a significant quantity of the drug to be released from the polymer matrix at too slow a rate. The loss of effectiveness may be compensated for by using a particularly strong modifier which will continue to work at low concentrations. In systems where the modifier is an acid or base, for example, a strong modifier will be one with a low pK.sub.a or pK.sub.b, respectively. High strength modifiers, however, can compromise the stability of acid- or base-sensitive drugs in the polymer system and, depending on the modifier, raise physiological risks and toxicity questions by releasing free quantities of modifier when administered to a patient.
Additionally, prior art modifiers are often not satisfactory due to the fact that they have been incorporated into the polymer in such a way that they are not mixed with the polymer on a molecular level but are present in a separate phase, which is dispersed on a supra-molecular level through the polymer matrix. This leads to a loss of efficiency and to the use of higher strength modifiers. Also, the high strength acid or base modifier, being in a separate phase from the polymer, is available to come into contact with and adversely affect drugs or other agents present in the polymer matrix which are sensitive to the modifier.
The present invention addresses these and other disadvantages and shortcomings of these and other methods of regulating the biodegradation rate of polymer matrices.